Ketoprofen 1-Alkylazacycloalkan-2-one Esters as Dermal Prodrugs: In Vivo and In Vitro Evaluations
Ketoprofen 1-Alkylazacycloalkan-2-one Esters as Dermal Prodrugs: In Vivo and In Vitro Evaluations
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DOI：
10.1081/ddc-120016726
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发表时间：
2003-01
影响因子：
3.4
通讯作者：
F. Bonina;N. Santagati;C. Puglia
中科院分区：
文献类型：
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作者：
F. Bonina;N. Santagati;C. Puglia
摘要合成了6个新的酮洛芬1-烷基氮杂环烷-2-酮酯（1-6），并评价了其作为酮洛芬经皮给药前药的潜力。用实验亲脂指数（logk ′）和计算的ClogP测定了它们的亲脂性。进行体外实验以评价这些新酮洛芬衍生物的化学和酶稳定性以及通过离体人皮肤的渗透。此外，我们研究了酯5的体内局部抗炎活性，其显示出最好的体外特征，评估了该化合物抑制健康人类志愿者的烟酸甲酯诱导的皮肤红斑的能力。与母体药物（酮洛芬）相比，酯1-6显示出增加的亲脂性，在pH 7.4的磷酸盐缓冲液中具有良好的稳定性，并且易于被猪酯酶水解。体外经皮吸收研究的结果表明，在所有合成的酯中，只有酯1和5的药物透过皮肤的累积量高于局部应用酮洛芬后获得的累积量。在体内的结果表明，一个有趣的延迟和持续的活性酯5，与母体药物相比。
Abstract Six new 1-alkylazacycloalkan-2-one esters of ketoprofen (1–6) were synthesized and evaluated as potential dermal prodrugs of ketoprofen. Their lipophilicity by both experimental lipophilicity indices (log k′) and calculated ClogP was also determined. In vitro experiments were carried out to evaluate the chemical and enzymatic stability and permeation through excised human skin of these new ketoprofen derivatives. Furthermore, we investigated the in vivo topical anti-inflammatory activity of ester 5, which showed the best in vitro profile, evaluating the ability of this compound to inhibit methyl nicotinate-induced skin erythema on healthy human volunteers. Esters 1–6 showed increased lipophilicity compared with the parent drug (ketoprofen), good stability in phosphate buffer pH 7.4, and were readily hydrolyzed by porcine esterase. Results from in vitro percutaneous absorption studies showed that, among all esters synthesized, only for esters 1 and 5 did a higher cumulative amount of drug penetrate through the skin, compared with that obtained after topical application of ketoprofen. In vivo results showed an interesting delayed and sustained activity of ester 5, compared with the parent drugs.